bims-glucam 2022-10-23 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–10–23
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University

ERN1 dependent impact of glutamine and glucose deprivations on the pyruvate dehydrogenase genes expression in glioma cells.
Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.
Serial Room Temperature Crystal Loading, Data Collection, and Data Processing of Human Glutaminase C in Complex with Allosteric Inhibitors.
Glutamine synthetase limits b-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.
Glucose-6-phosphate dehydrogenase exerts anti-stress effects independently of its enzymatic activity.
Glutamine Transporter SLC1A5 Regulates Ionizing Radiation-Derived Oxidative Damage and Ferroptosis.
Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities.
Malignant transformation by oncogenic K-ras requires IDH2-mediated reductive carboxylation to promote glutamine utilization.
Metabolic regulation of immune responses to cancer.
Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.
Protective effects of glutamine on lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice.
Principles and functions of metabolic compartmentalization.

Endocr Regul. 2022 Oct 01. 56(4): 254-264

ERN1 dependent impact of glutamine and glucose deprivations on the pyruvate dehydrogenase genes expression in glioma cells.

Hanna O Shatokhina, Olena O Khita, Dmytro O Minchenko, Dariia O Tsymbal, Olha R Luzina, Serhiy V Danilovskyi, Myroslava Y Sliusar, Liudmyla O Levadna, Oleksandr H Minchenko.

  Objective. The aim of the present study was to investigate the expression of pyruvate dehydrogenase genes such as PDHA1, PDHB, DLAT, DLD, and PDHX in U87 glioma cells in response to glutamine and glucose deprivations in control glioma cells and endoplasmic reticulum to nucleus signaling 1 (ERN1) knockdown cells, the major endoplasmic reticulum (ER) stress signaling pathway, to find out whether there exists a possible dependence of these important regulatory genes expression on both glutamine and glucose supply as well as ERN1 signaling. Methods. The expression level of PDHA1, PDHB, DLAT, DLD, and PDHX genes was studied by real-time quantitative polymerase chain reaction in control U87 glioma cells (transfected by empty vector) and cells with inhibition of ERN1(transfected by dnERN1) after cells exposure to glucose and glutamine deprivations. Results. The data showed that the expression level of PDHA1, PDHB, DLAT, and DLD genes was down-regulated (more profound in PDHB gene) in control glioma cells treated with glutamine deprivation. At the same time, ERN1 knockdown modified the impact of glutamine deprivation on the expression level of all these genes in glioma cells: suppressed the sensitivity of PDHB and DLD genes expression and removed the impact of glutamine deprivation on the expression of PDHA1 and DLAT genes. Glucose deprivation did not significantly change the expression level of all studied genes in control glioma cells, but ERN1 knockdown is suppressed the impact of glucose deprivation on PDHX and DLD genes expression and significantly enhanced the expression of PDHA1 and PDHB genes. No significant changes were observed in the sensitivity of PDHX gene expression to glutamine deprivation neither in control nor ERN1 knock-down glioma cells. The knock-down of ERN1 removed the sensitivity of DLAT gene expression to glucose deprivation. Conclusion. The results of this investigation demonstrate that the exposure of control U87 glioma cells under glutamine deprivation significantly affected the expression of PDHA1, PDHB, DLAT, and DLD genes in a gene specific manner and that impact of glutamine deprivation was modified by inhibition of the ER stress signaling mediated by ERN1. At the same time, glucose deprivation affected the expression of PDHA1, PDHB, PDHX, and DLD genes in ERN1 knockdown glioma cells only. Thus, the expression of pyruvate dehydrogenase genes under glutamine and glucose deprivation conditions appears to be controlled by the ER stress signaling through ERN1.

Keywords:  ERN1 knockdown; U87 glioma cells; gene expression; glutamine and glucose deprivations; pyruvate dehydrogenase

DOI:  https://doi.org/10.2478/enr-2022-0027
PLoS One. 2022 ;17(10): e0276579

Inhibiting glutamine utilization creates a synthetic lethality for suppression of ATP citrate lyase in KRas-driven cancer cells.

Ahmet Hatipoglu, Deepak Menon, Talia Levy, Maria A Frias, David A Foster.

Metabolic reprogramming is now considered a hallmark of cancer cells. KRas-driven cancer cells use glutaminolysis to generate the tricarboxylic acid cycle intermediate α-ketoglutarate via a transamination reaction between glutamate and oxaloacetate. We reported previously that exogenously supplied unsaturated fatty acids could be used to synthesize phosphatidic acid-a lipid second messenger that activates both mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTOR complex 2 (mTORC2). A key target of mTORC2 is Akt-a kinase that promotes survival and regulates cell metabolism. We report here that mono-unsaturated oleic acid stimulates the phosphorylation of ATP citrate lyase (ACLY) at the Akt phosphorylation site at S455 in an mTORC2 dependent manner. Inhibition of ACLY in KRas-driven cancer cells in the absence of serum resulted in loss of cell viability. We examined the impact of glutamine (Gln) deprivation in combination with inhibition of ACLY on the viability of KRas-driven cancer cells. While Gln deprivation was somewhat toxic to KRas-driven cancer cells by itself, addition of the ACLY inhibitor SB-204990 increased the loss of cell viability. However, the transaminase inhibitor aminooxyacetate was minimally toxic and the combination of SB-204990 and aminooxtacetate led to significant loss of cell viability and strong cleavage of poly-ADP ribose polymerase-indicating apoptotic cell death. This effect was not observed in MCF7 breast cancer cells that do not have a KRas mutation or in BJ-hTERT human fibroblasts which have no oncogenic mutation. These data reveal a synthetic lethality between inhibition of glutamate oxaloacetate transaminase and ACLY inhibition that is specific for KRas-driven cancer cells and the apparent metabolic reprogramming induced by activating mutations to KRas.

DOI: https://doi.org/10.1371/journal.pone.0276579
Bio Protoc. 2022 Sep 20. pii: e4509. [Epub ahead of print]12(18):

Serial Room Temperature Crystal Loading, Data Collection, and Data Processing of Human Glutaminase C in Complex with Allosteric Inhibitors.

Shawn K Milano, Marian D Szebenyi, And Richard A Cerione.

  Cancer cells often overexpress glutaminase enzymes, in particular glutaminase C (GAC). GAC resides in the mitochondria and catalyzes the hydrolysis of glutamine to glutamate. High levels of GAC have been observed in aggressive cancers and the inhibition of its enzymatic activity has been shown to reduce their growth and survival. Numerous GAC inhibitors have been reported, the most heavily investigated being a class of compounds derived from the small molecule BPTES (bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide). X-ray structure determination under cryo-cooled conditions showed that the binding contacts for the different inhibitors were largely conserved despite their varying potencies. However, using the emerging technique serial room temperature crystallography, we were able to observe clear differences between the binding conformations of inhibitors. Here, we describe a step-by-step protocol for crystal handling, data collection, and data processing of GAC in complex with allosteric inhibitors using serial room temperature crystallography. Graphical abstract: Figure 1. Workflow for serial room temperature crystallography. Diagram showing the processing and scaling routine for crystals analyzed using serial room temperature crystallography.

Keywords:   BPTES ; GAC ; Glutaminase ; Glutamine metabolism ; Serial crystallography

DOI:  https://doi.org/10.21769/BioProtoc.4509
J Clin Invest. 2022 Oct 18. pii: e161408. [Epub ahead of print]

Glutamine synthetase limits b-catenin-mutated liver cancer growth by maintaining nitrogen homeostasis and suppressing mTORC1.

Weiwei Dai, Jianliang Shen, Junrong Yan, Alex J Bott, Sara Maimouni, Heineken Q Daguplo, Yujue Wang, Khoosheh Khayati, Jessie Yanxiang Guo, Lanjing Zhang, Yongbo Wang, Alexander Valvezan, Wen-Xing Ding, Xin Chen, Xiaoyang Su, Shenglan Gao, Wei-Xing Zong.

  Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As dysregulated urea cycle is implicated in cancer development, the impact of GS' ammonia clearance function has not been explored in cancer. Here we show that, oncogenic activation of beta-catenin led to decreased urea cycle and elevated ammonia waste burden. While beta-catenin induced the expression of GS, which is thought to be cancer-promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived non-essential amino acids (NEAAs), which subsequently stimulated mTORC1. Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While HCC patients, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.

Keywords:  Hepatology; Liver cancer; Metabolism

DOI:  https://doi.org/10.1172/JCI161408
J Biol Chem. 2022 Oct 12. pii: S0021-9258(22)01030-4. [Epub ahead of print] 102587

Glucose-6-phosphate dehydrogenase exerts anti-stress effects independently of its enzymatic activity.

Xiaohan Jin, Xuexue Li, Lifang Li, Benfu Zhong, Yang Hong, Jing Niu, Binghui Li.

  G6PD (Glucose-6-phosphate dehydrogenase) is the rate-limiting enzyme in the oxPPP (oxidative pentose phosphate pathway) that can generate cytosolic NADPH for biosynthesis and oxidative defense. Since cytosolic NADPH can be compensatively produced by other sources, the enzymatic activity-deficiency alleles of G6PD are well tolerated in somatic cells, but the effect of null mutations is unclear. Herein, we show that G6PD knockout sensitizes cells to the stresses induced by hydrogen peroxide, superoxide, hypoxia, and the inhibition of the electron transport chain. This effect can be completely reversed by the expressions of natural mutants associated with G6PD deficiency, even without dehydrogenase activity, exactly like the wild type G6PD. Furthermore, we demonstrate that G6PD can physically interact with AMPK (AMPK-activated protein kinase) to facilitate its activity, and directly bind to NAMPT (nicotinamide phosphoribosyltransferase) to promote its activity and maintain the NAD(P)H/NAD(P)+ homeostasis. These functions are necessary to the anti-stress ability of cells but independent of the dehydrogenase activity of G6PD. In addition, the wild type G6PD and naturally inactive mutant also can similarly regulate the metabolism of glucose, glutamine, fatty acid synthesis, and glutathione, and interact with the involved enzymes. Therefore, our findings reveal the previously unidentified functions of G6PD that can act as the important physiological neutralizer of stresses independently of its enzymatic activity.

Keywords:  G6PD; NADH homeostasis; NAMPT; oxidative stress; pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.jbc.2022.102587
Oxid Med Cell Longev. 2022 ;2022 3403009

Glutamine Transporter SLC1A5 Regulates Ionizing Radiation-Derived Oxidative Damage and Ferroptosis.

Zhuhui Yuan, Tong Liu, Xiao Huo, Hao Wang, Junjie Wang, Lixiang Xue.

Ionizing radiation-derived oxidative stress and ferroptosis are one of the most important biological effects on destroying the liver tumor, whereas radioresistance of liver tumor remains a leading cause of radiotherapy (RT) failure mainly because of the protective antiferroptosis, in which oxidative stress and subsequent lipid peroxidation are the key initiators. Thus, it is of great importance to overcome ferroptosis resistance to improve the therapeutic efficacy of RT in liver tumor patients. Irradiation-resistant HepG2 cells (HepG2-IRR) were established by long-term exposure to X-ray (2 to 8 Gy), and targeted metabolomics analysis revealed an obvious increase in intracellular amino acids in HepG2-IRR cells upon ferroptosis stress. Among these amino acids with obvious changes, N-acetylglutamine, a derivative of glutamine, is essential for the redox homeostasis and progression of tumor cells. Interestingly, the treatment of glutamine starvation could promote the ferroptosis effect significantly, whereas glutamine supplementation reversed the ferroptosis effect completely. Consistent with the changes in amino acids pattern, the glutamine transporter SLC1A5 was verified in liver tumor samples from TCGA training and validation cohorts as an independent prognostic amino acid-ferroptosis gene (AFG). A risk score for screening prognosis based on the SLC1A5, SLC7A11, ASNS, and TXNRD1 demonstrated that a high-risk score was correlated with poor survival. In vitro studies had shown that the knockdown of SLC1A5 resulted in a significant decrease in cell viability and promoted lipid peroxidation and oxidative damage introduced by irradiation (10 Gy). Collectively, our findings indicated that SLC1A5 may act as a suppressor gene against ferroptosis and can be a potential target for ionizing radiation mediated effects.

DOI: https://doi.org/10.1155/2022/3403009
Cancer Commun (Lond). 2022 Oct 20.

Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities.

Tongxin Ge, Xiang Gu, Renbing Jia, Shengfang Ge, Peiwei Chai, Ai Zhuang, Xianqun Fan.

  Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels. Epigenetic modifiers, chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic-metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

Keywords:  RNA epigenetics; cancer; epigenetics; metabolic reprogramming; therapy

DOI:  https://doi.org/10.1002/cac2.12374
Cancer Commun (Lond). 2022 Oct 17.

Malignant transformation by oncogenic K-ras requires IDH2-mediated reductive carboxylation to promote glutamine utilization.

Rui Liu, Panpan Liu, Huichang Bi, Jianhua Ling, Huiqin Zhang, Mingquan Zhang, Yumin Hu, Paul J Chiao, Peng Huang, Jinyun Liu.

DOI: https://doi.org/10.1002/cac2.12369
Cancer Biol Med. 2022 Oct 24. pii: j.issn.2095-3941.2022.0381. [Epub ahead of print]

Metabolic regulation of immune responses to cancer.

Jannis Wißfeld, Anke Werner, Xin Yan, Nora Ten Bosch, Guoliang Cui.

  The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of "editing" metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

Keywords:  Lipids; NK cells; T cells; amino acids; anti-tumor immunity; cancer; immunometabolism; metabolism

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2022.0381
Sci Signal. 2022 Oct 18. 15(756): eabj3490

Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.

Deborah Y Moss, Christopher McCann, Emma M Kerr.

Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.

DOI: https://doi.org/10.1126/scisignal.abj3490
Exp Biol Med (Maywood). 2022 Oct 19. 15353702221126562

Protective effects of glutamine on lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice.

Mengxin Yang, Xinyue Zhang, Shuang Zhao, Ruyue Shao, Kerui Fan, Kai Hu, Li Zhang, Yongqiang Yang.

  Fulminant hepatitis remains a critical health problem owing to its high mortality rate and the lack of effective therapies. An increasing number of studies have shown that glutamine supplementation provides protective benefits in inflammation-related disorders, but the pharmacological significance of glutamine in lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced fulminant hepatitis remains unclear. In the present study, the potential effects of glutamine on LPS/D-Gal-induced fulminant hepatitis were investigated. Pretreatment with glutamine decreased plasma activities of alanine and aspartate aminotransferases, and ameliorated hepatic morphological abnormalities in LPS/D-Gal-exposed mice. Glutamine pretreatment also inhibited LPS/D-Gal-induced tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production. In addition, glutamine pretreatment decreased the level of cleaved cysteinyl aspartate-specific proteinase 3 (caspase-3), suppressed the activities of caspase-3, caspase-8, and caspase-9, and reduced the number of cells positive for TdT-mediated dUTP nick-end labeling in LPS/D-Gal-challenged mice. Interestingly, post-treatment with glutamine also provided protective benefits against LPS/D-Gal-induced acute liver injury, although these effects were less robust than those of glutamine pre-treatment. Thus, glutamine may have potential value as a pharmacological intervention in fulminant hepatitis.

Keywords:  D-galactosamine; Glutamine; apoptosis; fulminant hepatitis; inflammation; lipopolysaccharide

DOI:  https://doi.org/10.1177/15353702221126562
Nat Metab. 2022 Oct;4(10): 1232-1244

Principles and functions of metabolic compartmentalization.

Liron Bar-Peled, Nora Kory.

Metabolism has historically been studied at the levels of whole cells, whole tissues and whole organisms. As a result, our understanding of how compartmentalization-the spatial and temporal separation of pathways and components-shapes organismal metabolism remains limited. At its essence, metabolic compartmentalization fulfils three important functions or 'pillars': establishing unique chemical environments, providing protection from reactive metabolites and enabling the regulation of metabolic pathways. However, how these pillars are established, regulated and maintained at both the cellular and systemic levels remains unclear. Here we discuss how the three pillars are established, maintained and regulated within the cell and discuss the consequences of dysregulation of metabolic compartmentalization in human disease. Organelles are increasingly emerging as 'command-and-control centres' and the increased understanding of metabolic compartmentalization is revealing new aspects of metabolic homeostasis, with this knowledge being translated into therapies for the treatment of cancer and certain neurodegenerative diseases.

DOI: https://doi.org/10.1038/s42255-022-00645-2